Anecdotal experience with nuclear accident victims has shown that with superior supportive care, individuals may survive the acute radiation syndromes (hematopoietic and gastrointestinal syndromes), but ultimately succumb to respiratory distress due to radiation pneumonitis/fibrosis as a delayed effect. At this time there s no FDA approved treatment for radiation pneumonitis/fibrosis. Therefore, the goal of this project is to finalize the development of a safe, effective, practical, and widely available medical countermeasure to mitigate and/or treat radiation-induced pulmonary injury by utilizing a Nrf2 activator, trifluoromethyl-2'-methoxychalone (TMC) developed at Johns Hopkins University (JHU). The rationale for Nrf2 activator as a medical countermeasure arises from a decade of research demonstrating that augmenting Nrf2 signaling will inhibit oxidative stress, apoptosis, aberrant immune response, and inflammation (the 4 key pathologic processes involved in radiation-induced pulmonary injury) by upregulating a broad spectrum of cytoprotective defenses including nearly all cellular antioxidants. The studies proposed here will be focused on further development of TCM. The objective of this proposal is to bring TMC towards pivotal efficacy studies under GLP guidelines in rodent and non-human primates for Investigational New Drug (IND) application and FDA approval under the Animal Rule. The proposal comprises seven specific Milestones and defines benchmarks for determining their success. Specifically, the studies are designed to determine the maximum tolerated dose (MTD), tissue and plasma PK, establish a pharmacodynamics assay based on the mechanism of the compound, and to define the optimal dose, treatment duration, and window of opportunity for initiation of TMC treatment to optimize therapeutic efficacy and maximally improve survival.